This is a pilot and feasibility study to examine a novel intervention using leptin in weight-reduced individuals who have undergone bariatric surgery but still remain obese. Leptin, a peptide hormone secreted from adipose tissue, is a regulator of food intake and energy expenditure. Administration of leptin resulted in profound weight reduction in the few reported cases of obese individuals with genetic leptin deficiency. However, most obese people have increased leptin levels. Such individuals are said to be in a 'leptin- resistant'state, whereby administration of physiological concentrations of leptin are ineffective at producing significant weight reduction. Weight loss by calorie restriction results in decreased leptin levels and is usually followed by weight regain likely due to changes induced by a relative 'leptin-deficient'state that act to return an individual to his or her original weight. In contrast, Roux-en-Y gastric bypass surgery (RYGBP) is more effective than diet alone in producing long-term reduction of body weight. Yet even after surgery there is a plateau in weight loss though the individual may still be obese and have or be at risk for obesity related morbidities. We have shown that plasma leptin levels are significantly lower in women after RYGBP compared with BMI-matched controls. This state of relative hypoleptinemia or leptin insufficiency suggests that post-RYGBP individuals may be in a leptin-sensitive state and, thus, would undergo further weight loss when administered doses of leptin that would not normally result in significant weight reduction. After RYGBP patients also have a decline in thyroid hormone levels (which are regulated in part by leptin) that may counteract an individual's attempt at further weight reduction. We have also shown that RYGBP is associated with changes in gut hormone secretion, such as increased levels of plasma glucagon-like peptide-1 (GLP-1). GLP-1 acts synergistically with leptin to cause greater satiation and decreased food intake in animals. Thus, RYGBP patients may be particularly suited to respond to leptin therapy. The main objective of this study is to test the hypothesis that administration of leptin to weight reduced, but still obese, individuals after RYGBP will result in a significant reduction in body weight compared with placebo treatment. This study also provides a unique opportunity to further define the effects of leptin on appetitive sensations and neuroendocrine axes involved in energy homeostasis. If results from this study support our hypothesis, then further studies will be undertaken to examine the use of leptin alone or in combination with other anorectic agents in RYGBP patients and in individuals who have undergone weight reduction by other means and are at high risk for weight regain. PUBLIC HEALTH RELEVANCE: The increasing prevalence of obesity and its related morbidities makes it imperative to develop effective treatments to achieve and maintain a reduced body weight. Unfortunately current options are often ineffective at producing long-term weight reduction. This proposal will determine if the hormone leptin can produce weight loss in individuals who have undergone weight loss surgery but are still obese and may provide a new strategy for long-term weight reduction with non-surgical modalities.